Is SETD5 p.Lys174Arg (c.521A>G) pathogenic?

SETD5 p.Lys174Arg (c.521A>G) is classified Conflicting classifications of pathogenicity in SETD5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1139); Ultra-rare (popmax 0.014%, amr).

How common is SETD5 p.Lys174Arg (c.521A>G) in the general population?

SETD5 p.Lys174Arg (c.521A>G) is ultra-rare (popmax 0.014%, amr) (gnomAD).

What do computational predictors say about SETD5 p.Lys174Arg (c.521A>G)?

AlphaMissense predicts likely benign (score 0.1139) — an in-silico prediction, not a clinical call.

SETD5 p.Lys174Arg

c.521A>G · rs375122657 · VCV252525

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1139	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.014% Admixed American · 8/57,292 alleles

Filtering AF 0.00688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00502%

Overall 0.00206% 33/1,598,098 alleles · ultra-rare exomes 30/1,445,764 · genomes 3/152,334 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.014%	7,161
Remaining individualsnot grpmax-eligible	0.00646%	15,489
European (non-Finnish)	0.00171%	58,598
African / African-American	0.00134%	74,710

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SETD5
Protein: p.Lys174Arg
Coding: c.521A>G
MANE Select: NM_001080517
dbSNP: rs375122657
Type: single nucleotide variant
Location: chr3:9435860 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 174: the 'disordered' region

Full SETD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD5 p.Lys174fs Pathogenic ★ same residue
SETD5 c.1441-1G>A Pathogenic ★★ same type
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same type
SETD5 c.2347-1G>A Pathogenic ★★ same type
SETD5 c.2347-7A>G Pathogenic ★★ same type
SETD5 c.3631+1G>A Pathogenic ★★ same type
SETD5 c.960-5C>G Pathogenic/Likely pathogenic ★★ same type
SETD5 p.Arg1001Ter Pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/setd5-p-lys174arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown